Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 9 Iron Metabolism and Its Disorders
of eALAS (rate limiting enzyme in porphyrin synthesis)
when the LIP is high, and decreasing eALAS synthesis
when the LIP is low.
Even though three different pathways are required for
hemoglobin synthesis in erythrocyte precursors and reticulocytes,
virtually no intermediates (iron, globin chains, or
heme) accumulate in the cytoplasm of these cells. Several
positive and negative feedback mechanisms account for the
balanced production of these hemoglobin components. As
already discussed, an increase in the LIP limits the uptake
of additional iron by decreasing TfR1 synthesis. The availability
of iron also limits, and thereby controls, heme synthesis.
Free “ uncommitted ” heme inhibits iron uptake by
erythroid cells and consequently heme synthesis. In addition,
free heme is essential for the synthesis of globin
chains at both the transcriptional and translational levels
( Koury and Ponka, 2004 ). Consequently, globin synthesis
does not occur in the absence of heme.
A heme exporter termed FLVCR is up-regulated on
colony-forming units-erythroid (CFU-E) progenitor cells.
It may provide a safety mechanism to prevent the accumulation
of toxic amounts of cytoplasmic heme before globin
synthesis is initiated. FLVCR is the cell surface receptor
for feline leukemia virus, subgroup C (FeLV-C). Cats
with FeLV-C infections develop erythroid aplasia because
of a block at the CFU-E stage of erythroid development.
It appears that the binding of FeLV-C to receptors on CFU-
E progenitor cells inhibits heme export and results in apoptosis
of these cells ( Quigley et al ., 2004 ).
In addition to the entry of iron into mitochondria for
incorporation into protoporphyrin IX to form heme, iron
is critical for Fe-S cluster biogenesis within mitochondria.
Fe-S clusters are important prosthetic groups for numerous
proteins involved in electron transfer, metabolic, and regulatory
processes. Although Fe-S clusters are formed within
mitochondria, Fe-S proteins are located in the nucleus and
cytoplasm of cells, as well as in mitochondria ( Lill et al .,
2006 ). Recent studies in zebra fish provide evidence for a
regulatory link between Fe-S cluster formation and heme
synthesis. In the absence of Fe-S clusters, IRP1 binds to
eALAS mRNA, which inhibits eALAS synthesis and heme
production ( Wingert et al ., 2005 ).
B. Iron Metabolism in Macrophages
In contrast to erythroid cells, virtually no iron enters macrophages
via plasma transferrin. Rather, nearly all iron enters
macrophages by the phagocytosis of aged or prematurely
damaged erythrocytes ( Fig. 9-6 ) ( Ponka and Richardson,
1997 ). Following phagocytosis, erythrocytes are lysed, and
hemoglobin is degraded to heme and globin. The microsomal
heme oxygenase reaction within macrophages degrades
heme and releases iron. Most of the iron from degraded
heme is quickly exported (half-life 34 min in dogs) from the
macrophage and bound to plasma transferrin for transport
FIGURE 9-6 Iron metabolism in macrophages. Nearly all iron enters
macrophages by the phagocytosis of aged or prematurely damaged erythrocytes.
Following phagocytosis, erythrocytes are lysed, and hemoglobin
is degraded to heme and globin. The microsomal heme oxygenase reaction
within macrophages degrades heme and releases iron to the labile
iron pool (LIP). Most of the released iron is exported from the macrophage
by ferroportin as ferrous iron, oxidized to ferric iron by ceruloplasmin
(Cp) in plasma, and bound to apotransferrin (aTf) to form monoferric
transferrin (mTf) or diferric transferrin (not shown). Hepcidin in plasma
inhibits iron export by interacting directly with ferroportin, leading to
ferroportin’s internalization and lysosomal degradation. Iron not rapidly
released to plasma is stored within macrophages as ferritin, which may be
degraded to hemosiderin within lysosomes.
to other cells (especially erythrocyte precursors in the bone
marrow). The export of iron from macrophages is mediated
by ferroportin and controlled by hepcidin as has been discussed
for enterocytes ( Verga Falzacappa and Muckenthaler,
2005 ). In contrast to enterocytes that utilize membranebound
hephaestin, macrophages utilize the copper-containing
plasma protein ceruloplasmin to oxidize Fe 2 ions to
Fe 3 ions for binding to transferrin in plasma ( Nemeth et al .,
2004b ). Iron not rapidly released to plasma is stored within
macrophages as ferritin and hemosiderin. Iron that is stored
within macrophages is released to plasma more slowly, with
a half-life of 7 days in dogs ( Fillet et al ., 1974 ). The mononuclear
phagocyte system accounts for much of the total
body iron stores. Iron in the storage pool turns over slowly
unless there is an increased need for iron for hemoglobin
synthesis ( Beutler, 2006b ). In addition to iron export by ferroportin,
a small amount of iron is apparently released as
ferritin. It is not clear whether this is secreted or simply represents
a “ leak ” from damaged cells ( Ponka et al ., 1998 ).
Macrophages can take up iron present in hemoglobinhaptoglobin
complexes and heme-hemopexin complexes
in plasma. Haptoglobin-hemoglobin complexes form following
intravascular hemolysis when released hemoglobin
binds with high affinity to the plasma glycoprotein
haptoglobin. Heme-hemopexin complexes can also form
secondary to intravascular hemolysis when hemoglobin
heme is released, but additional heme-containing proteins
(such as myoglobin) release heme that binds to the plasma
protein hemopexin. The hemoglobin-haptoglobin complex
undergoes endocytosis after binding to the hemoglobin
scavenger receptor CD163. Expression of this receptor is